1. Field
The present disclosure relates generally to the fields of polymers and nanoparticles. In particular, it relates to a polymer composition which comprises a nucleic acid. More particularly, it relates to polymers produced through ring opening polymerization for the delivery of the nucleic acid.
2. Description of Related Art
Gene silencing via the RNA Interference (RNAi) mechanism is a promising strategy to treat major diseases including cancer, genetic disorders, and viral infections. However, the success of siRNA-based therapies has been limited by the difficulty of delivering these highly anionic biomacromolecular drugs into cells (Whitehead et al., 2009). Polymers are an important class of materials for drug and nucleic acid delivery due to the versatility in constructing different nanostructures including micelles, polyplexes, dendrimers, and polymer-siRNA conjugates (Lee et al., 2011 and Parmar et al., 2014). The ability to control chemical functionality is an exciting feature of modern polymer science that enables precise design of drug delivery systems. Compared to lipid-based systems, the chemical and physical properties can be more extensively and precisely engineered (Tan et al., 2011). Aliphatic polyesters synthesized by ring-opening polymerization including polyglycolide, polylactide, polycaprolactone, and their copolymers have been approved by the FDA in a number of products (Albertsson and Varma, 2002). But since they lack the required functional groups for siRNA binding and release, new synthetic strategies are required to prepare functionalized polyesters. To date, functionalized lactones have generally been accessed via low-yielding, multi-step synthetic pathways that often involve protecting groups, thereby limiting the scale of monomer and polymer production. As a direct consequence, it is challenging to sufficiently modulate polymer functionality to achieve effective delivery. Thus, the present disclosure employs a strategy to prepare functional lactone monomers in one step from commercially available starting materials. Furthermore, the polymerization is scalable and rapid with high monomer conversion that enabled the synthesis and screening of a variety of copolymer compositions and led to the discovery of optimal delivery materials.
Ring-opening polymerization of functional monomers has emerged as the most versatile method to prepare clinically translatable degradable polyesters (Jerome and Lecomte, 2008, Pounder and Dove, 2010 and Tian et al., 2012). A variety of functional groups have been introduced into lactones; however, the direct polymerization of tertiary amine functionalized cyclic esters has remained elusive. Numerous studies of lipids and non-degradable polymers have implicated tertiary amines and alkyl chains as key functional groups for effective siRNA delivery (Akincw et al., 2008, Love et al., 2010, Siegwart et al., 2011, Jayaraman et al., 2012, Scholz and Wagner, 2012 and Nelson et al., 2013). Yet, their potential incapability with esters has made direct synthesis of degradable polymers with amino groups challenging. One strategy to overcome this issue has been to utilize step-growth polymerization. For example, poly((3-amino ester)s, (Lynn and Langer, 2000, Zugates et al., 2006 and Green et al., 2008) poly(4-hydroxy-L-proline ester), poly(D-glucaramidoamine), and cationic cyclodextrin-based polymers (Davis et al., 2010) have been synthesized either directly or by post-polymerization modification. Additional polymers are known in the literature (Jerome and Lecomte, 2008, Pounder and Dove, 2010, Tian et al., 2012, Tan et al., 2011, Albertsson and Varma, 2002, Green et al., 2008, Kanasty et al., 2013 and Hao et al., 2013). However, these methods do not offer control over molecular weight and molecular weight distribution. Direct synthesis using controlled chain growth polymerization methods offers greater control over polymer composition and the ability to make block copolymers. Other cationic polymers, such as polyethyleneimine (Philipp et al., 2009, Schroeder et al., 2012, Dahlman et al., 2014) and polylysine, have been widely used as nucleic acid carriers; however, application of these materials to in vivo disease models is often limited by their cytotoxicity and non-degradability. Since incorporating biodegradability will improve biocompatibility and facilitate elimination of materials used in biomedical applications, the development of degradable polymer-based siRNA delivery systems represents an important goal. As such, the development of a polymer containing the desired functional groups such as tertiary amines and alkyl groups is of particular interest.